Insulin resistance protects the heart from fuel overload in dysregulated metabolic states

Abstract

Reversing impaired insulin sensitivity has been suggested as treatment for heart failure. However, recent clinical evidence suggests the opposite. Here we present a line of reasoning in support of the hypothesis that insulin resistance protects the heart from the consequences of fuel overload in the dysregulated metabolic state of obesity and diabetes. We discuss pathways of myocardial fuel toxicity, as well as several layers of defense against fuel overload. Our reassessment of the literature suggests that in the heart, insulin-sensitizing agents result in an elimination of some of the defenses, leading to cytotoxic damage. In contrast, a normalization of fuel supply should either prevent or reverse the process. Taken together, we offer a new perspective on insulin resistance of the heart.

Keywords: insulin resistance; metabolism; obesity.

Fig. 1.

Metabolic regulation in the insulin resistant heart. In the normal heart, the control of substrate supply and demand primarily occurs at the level of the plasma membrane and the mitochondria. In 1963, Randle et al. (48) first described a mechanism of competition between fatty acids and glucose for mitochondrial oxidation that would lead to decreased glucose utilization in the presence of increased fatty acid concentrations (48) (red). Fatty acid-mediated inhibition of glucose utilization stems from the allosteric effects of metabolites whose concentration rise in response to increased β-oxidation. At the same time, the activity of phosphofructokinase (PFK), which catalyzes the rate-limiting step in glycolysis, is inhibited by citrate. The resulting increase in glucose 6-phosphate (Glc-6-P) levels in turn inhibits the activity of hexokinase (HK), and rates of glucose uptake are decreased. The mechanism for a reciprocal relation between glucose and fatty acid oxidation was first shown in the heart by McGarry et al. (39). Increased flux of glucose through the pyruvate dehydrogenase (PDH) complex inhibits β-oxidation through an increase in cytosolic malonyl-CoA, which acts as an inhibitor of the carnitine palmitoyltransferase 1 (CPT1) reaction (green). We propose that in the stressed heart, an additional level of control exists to limit excess substrate supply through inhibition of the insulin signaling pathway. As suggested by Shulman (52), an alternative mechanism for fatty acid-mediated inhibition of glucose uptake exists, in which the accumulation of fatty acid metabolites such as diacylglycerol, fatty acyl-CoA, and ceramides leads to the activation of novel PKC isoforms and to the inhibitory phosphorylation of insulin receptor substrates (IRSs) (purple). Recent studies by James and colleagues (27) and Beauloye and colleagues (5) suggest that both mitochondrial and cytosolic reactive oxygen species (ROS) decrease insulin sensitivity as a way to limit their own production (blue). Both mechanisms may therefore restore substrate homeostasis by decreasing the translocation of the glucose transporter GLUT4, and possibly of the fatty acid transporter CD36, at the sarcolemma. NOX2, NADPH oxidase 2; PI3K, phosphatidylinositol 3-kinase; FATP, fatty acid transport protein; ACL, ATP citrate lyase; ACC, acetyl-CoA carboxylase; Fru-1,6-P₂, fructose-2,6-bisphosphatase.